Abstract P6-03-15: MCL-1 confers oncogenic role in breast cancer through modulating drug resistance and cancer stemness by targeting MRP1

Triple negative breast cancer (TNBC) possesses poor prognosis mainly due to development of chemoresistance and lack of effective endocrine or targeted therapies. MiR-491-5p has been found to play a tumor suppressor role in many cancers including breast cancer. However, the precise role of miR-491-5p in TNBC has never been elucidated. In this study, we reported the novel tumor suppressor function of FOCAD/miR-491-5p in TNBC. High expression of miR-491-5p was found to be associated with better overall survival in breast cancer patients. We found that miR-491-5p could be an intronic microRNA processed form FOCAD gene. We are the first to demonstrate that both miR-491-5p and FOCAD function as tumor suppressors to inhibit cancer stemness, epithelial-mesenchymal transition, drug resistance, cell migration/invasion, and pulmonary metastasis etc. in TNBC. MiR-491-5p was first reported to directly target Rab interacting factor (RABIF) to downregulate RABIF-mediated TNBC cancer stemness, drug resistance, cell invasion, and pulmonary metastasis via matrix metalloproteinase (MMP) signaling. High expression of RABIF was found to be correlated with poor clinical outcomes of breast cancer and TNBC patients. Our data indicated that miR-491-5p and RABIF are potential prognostic biomarkers and targeting the novel FOCAD/miR-491-5p/RABIF/MMP signaling pathway could serve as a promising strategy in TNBC treatment.

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CDK12 Promotes Breast Cancer Progression and Maintains Stemness by Activating c-myc/β -catenin Signaling

Current Cancer Drug Targets ◽

10.2174/1568009619666191118113220 ◽

2020 ◽

Vol 20 (2) ◽

pp. 156-165 ◽

Cited By ~ 3

Author(s):

Fang Peng ◽

Chuansheng Yang ◽

Yanan Kong ◽

Xiaojia Huang ◽

Yanyu Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Lung Metastasis ◽

Xenograft Model ◽

Breast Cancer Cell Lines ◽

Cell Renewal ◽

Cancer Stemness ◽

Mesenchymal Transition ◽

Potential Biomarker

Background: CDK12 is a promising therapeutic target in breast cancer with an effective ability of maintaining cancer cell stemness. Objective: We aim to investigate the mechanism of CDK12 in maintaining breast cancer stemness. Methods: CDK12 expression level was accessed by using RT-qPCR and IHC. CDK12-altered breast cancer cell lines MDA-MB-231-shCDK12 and SkBr-3-CDK12 were then established. CCK8, colony formation assays, and xenograft model were used to value the effect of CDK12 on tumorigenicity. Transwell assay, mammosphere formation, FACS, and lung metastasis model in vivo were determined. Western blot further characterized the mechanism of CDK12 in breast cancer stemness through the c-myc/β-catenin pathway. Results: Our results showed a higher level of CDK12 exhibited in breast cancer samples. Tumor formation, cancer cell mobility, spheroid forming, and the epithelial-mesenchymal transition will be enhanced in the CDK12high group. In addition, CDK12 was associated with lung metastasis and maintained breast cancer cell stemness. CDK12high cancer cells presented higher tumorigenicity and a population of CD44+ subset compared with CDK12low cells. Our study demonstrated c-myc positively expressed with CDK12. The c-myc/β-catenin signaling was activated by CDK12, which is a potential mechanism to initiate breast cancer stem cell renewal and may serve as a potential biomarker of breast cancer prognosis. Conclusion: CDK12 overexpression promotes breast cancer tumorigenesis and maintains the stemness of breast cancer by activating c-myc/β-catenin signaling. Inhibiting CDK12 expression may become a potential therapy for breast cancer.

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A common transition in multi-drug resistance gene and risk of breast cancer: A genetic association study with an in silico-analysis

Bioscience Biotechnology Research Communications ◽

10.21786/bbrc/9.4/11 ◽

2016 ◽

Vol 9 (4) ◽

pp. 643-652

Author(s):

Davood Kheirkhah ◽

Mohammad Karimian

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Association Study ◽

Resistance Gene ◽

In Silico ◽

Genetic Association Study ◽

In Silico Analysis ◽

Multi Drug Resistance ◽

Common Transition ◽

Silico Analysis

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Clinical applications of circulating tumor DNA in monitoring breast cancer drug resistance

Future Oncology ◽

10.2217/fon-2019-0760 ◽

2020 ◽

Vol 16 (34) ◽

pp. 2863-2878

Author(s):

Yang Liu ◽

Qian Du ◽

Dan Sun ◽

Ruiying Han ◽

Mengmeng Teng ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Digital Pcr ◽

Circulating Tumor Dna ◽

Resistance Mechanisms ◽

Clinical Applications ◽

Current Status ◽

Cancer Drug ◽

Genomic Alteration ◽

Tumor Dna

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. Unfortunately, treatments often fail because of the development of drug resistance, the underlying mechanisms of which remain unclear. Circulating tumor DNA (ctDNA) is free DNA released into the blood by necrosis, apoptosis or direct secretion by tumor cells. In contrast to repeated, highly invasive tumor biopsies, ctDNA reflects all molecular alterations of tumors dynamically and captures both spatial and temporal tumor heterogeneity. Highly sensitive technologies, including personalized digital PCR and deep sequencing, make it possible to monitor response to therapies, predict drug resistance and tailor treatment regimens by identifying the genomic alteration profile of ctDNA, thereby achieving precision medicine. This review focuses on the current status of ctDNA biology, the technologies used to detect ctDNA and the potential clinical applications of identifying drug resistance mechanisms by detecting tumor-specific genomic alterations in breast cancer.

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Quercetin and doxorubicin co-encapsulated biotin receptor-targeting nanoparticles for minimizing drug resistance in breast cancer

Oncotarget ◽

10.18632/oncotarget.8607 ◽

2016 ◽

Vol 7 (22) ◽

pp. 32184-32199 ◽

Cited By ~ 37

Author(s):

Li Lv ◽

Chunxia Liu ◽

Chuxiong Chen ◽

Xiaoxia Yu ◽

Guanghui Chen ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Receptor Targeting

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Clinical Identification of Dysregulated Circulating microRNAs and Their Implication in Drug Response in Triple Negative Breast Cancer (TNBC) by Target Gene Network and Meta-Analysis

Genes ◽

10.3390/genes12040549 ◽

2021 ◽

Vol 12 (4) ◽

pp. 549

Author(s):

Amal Qattan ◽

Taher Al-Tweigeri ◽

Wafa Alkhayal ◽

Kausar Suleman ◽

Asma Tulbah ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Triple Negative Breast Cancer ◽

Drug Response ◽

Triple Negative ◽

Meta Analysis ◽

Integrated Analysis ◽

Circulating Mirnas ◽

Persistent Problem ◽

Network Analyses

Resistance to therapy is a persistent problem that leads to mortality in breast cancer, particularly triple-negative breast cancer (TNBC). MiRNAs have become a focus of investigation as tissue-specific regulators of gene networks related to drug resistance. Circulating miRNAs are readily accessible non-invasive potential biomarkers for TNBC diagnosis, prognosis, and drug-response. Our aim was to use systems biology, meta-analysis, and network approaches to delineate the drug resistance pathways and clinical outcomes associated with circulating miRNAs in TNBC patients. MiRNA expression analysis was used to investigate differentially regulated circulating miRNAs in TNBC patients, and integrated pathway regulation, gene ontology, and pharmacogenomic network analyses were used to identify target genes, miRNAs, and drug interaction networks. Herein, we identified significant differentially expressed circulating miRNAs in TNBC patients (miR-19a/b-3p, miR-25-3p, miR-22-3p, miR-210-3p, miR-93-5p, and miR-199a-3p) that regulate several molecular pathways (PAM (PI3K/Akt/mTOR), HIF-1, TNF, FoxO, Wnt, and JAK/STAT, PD-1/PD-L1 pathways and EGFR tyrosine kinase inhibitor resistance (TKIs)) involved in drug resistance. Through meta-analysis, we demonstrated an association of upregulated miR-93, miR-210, miR-19a, and miR-19b with poor overall survival outcomes in TNBC patients. These results identify miRNA-regulated mechanisms of drug resistance and potential targets for combination with chemotherapy to overcome drug resistance in TNBC. We demonstrate that integrated analysis of multi-dimensional data can unravel mechanisms of drug-resistance related to circulating miRNAs, particularly in TNBC. These circulating miRNAs may be useful as markers of drug response and resistance in the guidance of personalized medicine for TNBC.

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LncRNA DLX6-AS1 Contributes to Epithelial–Mesenchymal Transition and Cisplatin Resistance in Triple-negative Breast Cancer via Modulating Mir-199b-5p/Paxillin Axis

Cell Transplantation ◽

10.1177/0963689720929983 ◽

2020 ◽

Vol 29 ◽

pp. 096368972092998 ◽

Cited By ~ 1

Author(s):

Chuang Du ◽

Yan Wang ◽

Yingying Zhang ◽

Jianhua Zhang ◽

Linfeng Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Drug Resistance ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cisplatin Resistance ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Expression Levels

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer types with high recurrence, metastasis, and drug resistance. Recent studies report that long noncoding RNAs (lncRNAs)-mediated competing endogenous RNAs (ceRNA) play an important role in tumorigenesis and drug resistance of TNBC. Although elevated lncRNA DLX6 antisense RNA 1 (DLX6-AS1) has been observed to promote carcinogenesis in various cancers, the role in TNBC remained unclear. In this study, expression levels of DLX6-AS1 were increased in TNBC tissues and cell lines when compared with normal tissues or breast fibroblast cells which were determined by quantitative real-time PCR (RT-qPCR). Then, CCK-8 assay, cell colony formation assay and western blot were performed in CAL-51 cells transfected with siRNAs of DLX6-AS1 or MDA-MB-231 cells transfected with DLX6-AS1 over expression plasmids. Knock down of DLX6-AS1 inhibited cell proliferation, epithelial-mesenchymal transition (EMT), decreased expression levels of BCL2 apoptosis regulator (Bcl-2), Snail family transcriptional repressor 1 (Snail) as well as N-cadherin and decreased expression levels of cleaved caspase-3, γ-catenin as well as E-cadherin, while up regulation of DLX6-AS1 had the opposite effect. Besides, knockdown of DLX6-AS1 in CAL-51 cells or up regulation of DLX6-AS1 in MDA-MB-231 cells also decreased or increased cisplatin resistance of those cells analyzed by MTT assay. Moreover, by using dual luciferase reporter assay, RNA immunoprecipitation and RNA pull down assay, a ceRNA which was consisted by lncRNA DLX6-AS1, microRNA-199b-5p (miR-199b-5p) and paxillin (PXN) was identified. And DLX6-AS1 function through miR-199b-5p/PXN in TNBC cells. Finally, results of xenograft experiments using nude mice showed that DLX6-AS1 regulated cell proliferation, EMT and cisplatin resistance by miR-199b-5p/PXN axis in vivo. In brief, DLX6-AS1 promoted cell proliferation, EMT, and cisplatin resistance through miR-199b-5p/PXN signaling in TNBC in vitro and in vivo.

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